First stereoselective total synthesis and biological evaluation of amphidinin B and Its analogues

Article abstract of DOI:10.1002/ejoc.201001205

A highly stereoselective first total synthesis of amphidinin B is described. The key steps involved in this synthesis are the generation of the exo-double bond in the C¹-C⁹ segment, the Barbier allylation, enzymatic kinetic resolutio

Full text of DOI:10.1002/ejoc.201001205

FULL PAPER
DOI: 10.1002/ejoc.201001205
First Stereoselective Total Synthesis and Biological Evaluation of Amphidinin
B and Its Analogues
Jhillu S. Yadav,*[a] A. Srinivas Reddy,[a,b] Ch. Suresh Reddy,[a] Basi V. Subba Reddy,[a]
Venkateshwarlu Saddanapu,[c] and Anthony Addlagatta[c]
Keywords: Natural products / Total synthesis / Diastereoselectivity / Macrocycles / Chemoselectivity / Oxidation / Enzyme
catalysis
A highly stereoselective first total synthesis of amphidinin B
is described. The key steps involved in this synthesis are the
generation of the exo-double bond in the C1–C9 segment,
the Barbier allylation, enzymatic kinetic resolution, and the
construction of the C10–C21 segment by Sharpless asymmet-
ric epoxidation, base-induced epoxide ring-opening, radical
cyclization, diastereoselective reduction of the exo-cyclic
double bond, one-pot allylation followed by debenzylation,
Evans alkylation, and Yamaguchi esterification.
Introduction
Marine dinoflagellates of the genus Amphidinium have
been recognized as a source of novel secondary metabolites
with interesting biological activity.[1] Despite their common
origin and high toxicity against various cancer cell lines,
the linear polyketides possess a high degree of structural
diversity, incorporating many variegated molecular scaf-
folds.[2] Amphidinin B (2) was isolated from the extracts of
the strain Y-56 of the dinoflagellate Amphidinium sp., which
is a linear polyketide possessing a trisubstituted tetra-
hydrofuran moiety, an exo-methylene, three branched
methyl groups and two carboxyl groups. The structure of 2
was established by extensive NMR spectroscopic studies
and the absolute stereochemistry was established by modi-
fied Mosher’s method.[3] The backbone of 2 was the same
as the carbon framework of the 19-membered macrolide,
amphidinolide T1 (1).[4] Biogenetically, amphidinin B (2)
may be related to amphidinolide T1 (1) (Scheme 1).
Scheme 1. Structures of amphidinolide T1 (1) and amphidinin B
(2).
Because of the low amounts available for biological selective approach to the total synthesis of amphidinin B
evaluation and because of its unique molecular architecture, (2).
amphidinin B (2) has attracted significant attention from a
Our retrosynthetic analysis of amphidinin B (2) is shown
number of synthetic chemists. In a continuation of our syn- in Scheme 2. The formation of the amphidinin B was envis-
thesis of complex natural products, such as amphidinolide aged starting from terminal diol 3, which could, in turn, be
T1 (1),[5] we herein report a novel, convergent and stereo- obtained by Yamaguchi esterification[6] between the trisub-
stituted tetrahydrofuran fragment 4 and the homoallyl ether
[a] Division of Organic Chemistry, Indian Institute of Chemical fragment 5. Synthons 4 and 5 could be obtained from 6 and
Technology (CSIR),
7, respectively.
Hyderabad 500607, India
The synthesis of compound 4 began from the known
mono-benzyl ether 6 (Scheme 3), which was oxidized to the
corresponding aldehyde and further homologated by a two-
carbon Wittig olefination to afford α,β-unsaturated ester 8
(E isomer) as the sole product (81% over two steps). Re-
duction of compound 8 with LiAlH4/AlCl3 afforded the al-
lylic alcohol in 80% yield. Sharpless asymmetric epoxid-
Fax: +91-40-27160387
E-mail: yadavpub@iict.res.in
[b] University of Hyderabad,
Hyderabad 500046, India
[c] Center for Chemical Biology, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001205.
696
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Amphidinin B and Analogues
chloride in the presence of NaHCO3 under reflux condi-
tions, followed by subsequent base-induced dehydrohaloge-
nation using the methodology developed by us,[8] gave alk-
ynol 10 in 88% overall yield. Compound 10 was then reacted
with ethyl vinyl ether and N-bromosuccinimide (NBS) to
afford the corresponding bromo acetal, which, upon radical
cyclization[9] in the presence of nBu3SnH and 2,2Ј-azobis-
(isobutyronitrile) (AIBN) in refluxing benzene, afforded
homoallylic lactol ether 11 in 75% overall yield for the two
steps. Diastereoselective reduction of compound 11 with
NaBH4 and NiCl2·6H2O[10] in methanol followed by Jones
oxidation[11] afforded a mixture of syn and anti isomers 12
in an 8:2 ratio (80% yield over two steps), which were sepa-
rated by column chromatography.
Reduction of the syn-lactone with diisobutylaluminum
hydride (DIBAL-H) gave the lactol, which was sub-
sequently treated with allyltrimethylsilane in the presence of
a stiochiometric amount of iodine to accomplish allylation
with a concomitant debenzylation,[12] resulting in the for-
mation of the allylated product 13 in 83% yield as the only
product. The primary hydroxyl group of 13 was converted
Scheme 2. Retrosynthetic analysis of amphidinin B.
ation of the allyl alcohol using (+)-diisopropyl tartrate [(+)- into the carboxyl group by oxidation with 2,2,6,6-tetra-
DIPT], Ti(OiPr)4 and TBHP at –20 °C gave the epoxy methylpiperidine-1-oxyl (TEMPO) and [bis(acetoxy)iodo]-
alcohol 9 in 91% yield with 94% ee.[7] Treatment of com- benzene (BAIB) in a mixture of dichloromethane and
pound 9 with triphenylphosphane (TPP) and carbon tetra- water.[13] The resulting acid was coupled with chiral (S)-
Scheme 3. Synthesis of segment 4.
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J. S. Yadav et al.
FULL PAPER
oxazolidin-2-one using mixed anhydride conditions, to fur- jected to base-induced reductive elimination using nBuLi
nish 14 in 81% yield over two steps.[14] Diastereoselective as base and AlH3 (alane) as reducing agent to afford the
alkylation of the sodium-enolate of 14 with iodomethane, substituted allyl alcohol 18 exclusively in 60% yield.[17] The
followed by reductive cleavage of the chiral auxiliary, af- conversion of substituted allyl alcohol 18 into the corre-
forded alcohol 15 as the only isomer in 69% overall yield sponding allyl bromide was achieved by using TPP/CBr4.
(Scheme 1). The resulting hydroxyl group was converted The resulting allyl bromide was treated with n-butanal un-
into its tert-butyldimethylsilyl (TBS) ether followed by dihy- der conditions developed by Barbier[18] to afford a racemic
droxylation with a catalytic amount of OsO4 and a stoichio- homoallyl alcohol 19 in 68% yield over two steps. Enzy-
metric amount of 4-methylmorpholine N-oxide (NMO). matic kinetic resolution of 19 using lipase PS-C “Amano”
The oxidative cleavage of the diol using NaIO4 gave alde- II afforded (R)-homoallylic acetate 21 (38% yield with 98%
hyde 16 in 70% yield over three steps.[15] The resulting alde- ee).[19] The undesired isomer 20 was converted into the re-
hyde was reduced with NaBH4 to afford the corresponding quired isomer by oxidation, followed by reduction and a
alcohol, which was subsequently protected as its p-meth- subsequent enzymatic resolution. Deacetylation of 21 with
oxybenzyl (PMB) ether using p-methoxybenzyl bromide sodium methoxide gave the segment 5 in 95% yield.
(PMBBr) and sodium hydride to afford 17 in 76% over two
With the successful synthesis of the two fragments 4 and
steps. Exposure of TBS ether 17 to HF/Py complex afforded 5, the next task was to assemble both of the segments using
the primary hydroxyl compound, which, on subsequent oxi- an intermolecular Yamaguchi esterification to obtain com-
dation with TEMPO/BAIB,[13] gave acid 4 in 88% yield pound 22 in 85% yield (Scheme 5).[6] Oxidative removal of
(two steps).
the terminal benzyl and p-methoxybenzyl groups in 22
The synthesis of segment 5 (Scheme 4) began with mono- using 30 equiv. of 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
benzyl ether 7, which can be prepared from the commer- none (DDQ) in a mixture of dichloromethane and water
cially available methyl (S)-3-hydroxy-2-methylpropionate.[16] gave the terminal diol 3 in 93% yield.[20] Oxidation of the
Iodination of 7 with TPP, imidazole and molecular iodine primary hydroxyl groups of 3 to the corresponding carboxyl
afforded the corresponding iodo compound in 90% yield, groups was achieved using TEMPO/BAIB to afford amphi-
which was alkylated with diethyl malonate and then sub- dinin B (2) in 90% yield.[21] The spectral (1H and 13C
NMR) and analytical data were in good agreement with
the data reported in the literature for the natural product.[3]
Amphidinin B (2) was converted into its corresponding
methyl ester using diazomethane to afford 23 in 94% yield.
Synthesis of compound 25 began with segment 5. Protec-
tion of the secondary hydroxyl group in segment 5 as its
TBS ether gave 24 in 91% yield (Scheme 6). Treatment of
compound 24 with lithium/naphthalene[22] afforded the pri-
mary hydroxyl compound, which, on subsequent oxidation
with TEMPO/BAIB, gave compound 25 in 93% yield (two
steps).
In a recent report, amphidinolide T1 (1) was shown to
exhibit cytotoxicity (IC50) effects on mammalian cells in the
micromolar range. To further understand the effects of am-
phidinin B (2) and its synthetic intermediates, the efficacy
Scheme 4. Synthesis of the segment 5.
Scheme 5. Completion of total synthesis of amphidinin B (2).
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Amphidinin B and Analogues
Column chromatography was carried out using silica gel (60–
120 mesh) and (230–400 mesh). Specific optical rotations [α]D are
given in 10–1 deg·cm2·g–1. Infrared spectra were recorded either in
CHCl3 or neat (as mentioned) and are reported in wave numbers
(cm–1). 1H and 13C NMR chemical shifts are reported in ppm
downfield from tetramethylsilane and coupling constants (J) are
reported in Hertz. The following abbreviations are used to desig-
nate signal multiplicity: s = singlet, d = doublet, t = triplet, q =
quartet, quint = quintet, m = multiplet, and br = broad.
7-(Benzyloxy)heptanal (6a): To a solution of oxalyl chloride
(6.1 mL, 71.53 mmol) in CH2Cl2 (60 mL) at –78 °C was added di-
methyl sulfoxide (10.8 mL, 152.56 mmol) over 20 min. The reaction
mixture was stirred for an additional 15 min and then alcohol 6
(10.63 g, 47.66 mmol) dissolved in CH2Cl2 (30 mL) was added
slowly by using a cannula. After 30 min, triethylamine (33.2 mL,
238.4 mmol) was added dropwise to the reaction mixture. The reac-
tion was allowed to warm to r.t. over 1 h. After completion of the
reaction (monitored by TLC), it was quenched with water (120 mL)
and the aqueous phase was extracted with CH2Cl2 (2ϫ50 mL).
The combined organic layers were washed with brine, dried with
anhydrous Na2SO4, concentrated under reduced pressure and puri-
fied by column chromatography (ethyl acetate/hexane, 1:9) to af-
ford aldehyde 6a (8.4 g, 90%) as a colorless liquid. 1H NMR
(300 MHz, CDCl3): δ = 9.76 (s, 1 H, CHO), 7.37–7.22 (m, 5 H,
PhH), 4.49 (s, 2 H, OCH2Ph), 3.45 (t, J = 6.0 Hz, 2 H, CH2OBn),
2.43 (td, J = 7.5, 1.5 Hz, 2 H, CH2CHO), 1.72–1.57 (m, 4 H,
(CH2)2), 1.49–1.31 (m, 4 H, (CH2)2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.6, 138.7, 128.2, 127.5, 127.4, 72.8, 70.2, 43.8, 29.5,
Scheme 6. Synthesis of compound 25.
of these compounds were tested against MCF-7, a breast
cancer cell line. The 3-(4,5-dimethylthiazol-2-yl)-2,5-di-
phenyltetrazolium bromide (MTT) assay was performed by
following the previously reported protocol in 96-well
plates.[23] The IC50 values for the compounds are summa-
rized in Table 1. Surprisingly, amphidinin B (2), with the
terminal carboxylic acids, displayed about 100 times better
activity than its cyclic analog. Esterified amphidinin B (23)
or reduced amphidinin B (3) decreased the efficiency of am-
phidinin B (2) by ten-fold and still displayed better activity
than amphidinolide T1 (1). To summarize, the acyclic com-
pounds show much better efficiency in killing cancer cells
than their cyclic analogs. Moreover, when the two frag-
ments of amphidinin B (2) were tested separately, only one
(fragment 25), with the aliphatic chain, displayed efficiency
as good as amphidinolide T1 (1); the second half (fragment
4) is ineffective even at 1 mm concentration (Table 1).
28.9, 25.9, 22.0 ppm. IR (neat): ν = 2933, 2857, 1723, 1099, 737,
˜
697 cm–1. HRMS (ESI): calcd. for C14H21O2 [M + H]+ 221.1541;
found 221.1534.
Ethyl (E)-9-(Benzyloxy)-2-nonenoate (8): To a stirred solution of
aldehyde 6a (8.08 g, 36.74 mmol) in benzene (100 mL), was added
Ph3P=CHCO2Et (19.18 g, 55.11 mmol) in one portion. The reac-
tion was heated to reflux for 4 h at 80 °C. Upon completion of the
reaction (monitored by TLC), the reaction mixture was concen-
trated under reduced pressure. Purification by flash column
chromatography (ethyl acetate/hexane, 0.5:9.5) afforded α,β-unsat-
urated ester 8 (9.82 g, 90%) as a colorless liquid. 1H NMR
(200 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H, PhH), 7.00–6.82 (m, 1
H, CH=CHCO2Et), 5.77 (d, J = 15.5 Hz, 1 H, CH=CHCO2Et),
4.47 (s, 2 H, OCH2Ph), 4.16 (q, J = 6.9 Hz, 2 H, OCH2CH3),
Table 1. Biological activity of amphidinin B and its analogues.
Entry
Compound
IC50 [μm]
1
2
3
4
5
6
1
2
73.5
0.83
1000
9.9
99.7
7.9
4
23
25
3
3.42 (t,
J = 6.9 Hz, 2 H, CH2OBn), 2.27–2.13 (m, 2 H,
Conclusions
CH2CH=CHCO2Et), 1.66–1.34 (m, 8 H, (CH2)4), 1.30 (t, J =
6.9 Hz, 3 H, OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
185.8, 168.3, 157.8, 147.5, 146.7, 146.6, 140.5, 92.0, 89.5, 79.2, 51.2,
A highly convergent and stereoselective first total synthe-
sis of amphidinin B (2) has been achieved that confirmed
the absolute configuration and provided sufficient quanti-
ties for biological evaluation. The stereocenters of the sub-
stituted tetrahydrofuran moiety were obtained by Sharpless
asymmetric epoxidation, diastereoselective reduction of the
exocyclic double bond, and allylation of the five-membered
ring oxa-carbenium ion using our developed methodology.
48.8, 48.1, 47.1, 45.1, 33.4 ppm. IR (neat): ν = 2932, 2856, 1719,
˜
1653, 1267, 1183, 1101, 737, 699 cm–1. HRMS (ESI): calcd. for
C18H26O3Na [M + Na]+ 313.1779; found 313.1771.
(E)-9-(Benzyloxy)-2-nonen-1-ol (8a): To a stirred suspension of Li-
AlH4 (1.67 g, 44.27 mmol) in anhydrous Et2O (60 mL) at 0 °C un-
der an N2 atmosphere, was added slowly a solution of AlCl3
(1.97 g, 14.75 mmol) in Et2O (20 mL). The reaction mixture was
stirred at the same temperature for 30 min. To this stirred suspen-
sion, was added dropwise a solution of ester 8 (8.57 g, 29.52 mmol)
in anhydrous Et2O (20 mL) over a period of 10 min and stirred
at 0 °C for an additional 1 h. Upon completion of the reaction
(monitored by TLC), the reaction mixture was quenched with ice
pieces and filtered through Celite and the residue was washed with
hot ethyl acetate. The combined organic layer was dried with anhy-
Experimental Section
General Remarks: Air- and/or moisture-sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon in
oven- or flame-dried glassware. All anhydrous solvents were dis-
tilled prior to use: THF, benzene, toluene, and diethyl ether from
Na and benzophenone; CH2Cl2 from CaH2; MeOH, EtOH from drous Na2SO4, concentrated and purification by column
Mg cake. Commercial reagents were used without purification. chromatography (ethyl acetate/hexane, 2:8) to give the allyl alcohol
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J. S. Yadav et al.
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8a (5.86 g, 80%) as a viscous liquid. 1H NMR (200 MHz, CDCl3):
δ = 7.33–7.21 (m, 5 H, PhH), 5.65–5.57 (m, 2 H, CH=CH), 4.47
(s, 2 H, OCH2Ph), 4.02 (d, J = 3.9 Hz, 2 H, CH=CHCH2OH), 3.43
by the slow addition of freshly cut fine lithium metal pieces (0.64 g,
92.0mmol), and the mixture was stirred for 30 min. A solution of
epoxy chloride 9a (4.28 g, 15.34 mmol) in THF (2.5 mL) was added
H, dropwise at –78 °C. After completion of the reaction (monitored
(t,
J
=
7.0 Hz,
2
H, CH2OBn), 2.09–1.96 (m,
2
CH2CH=CHCH2OH), 1.69–1.51 (m, 3 H, CH2CH), 1.46–1.24 (m, by TLC), the reaction mixture was quenched by addition of some
5 H, (CH2)2CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.7,
133.0, 129.0, 128.3, 127.6, 127.5, 72.9, 70.4, 63.6, 32.2, 29.6, 29.1,
solid ammonium chloride and the ammonia was allowed to evapo-
rate. The residue was dissolved in diethyl ether and filtered. The
filtrate was dried with Na2SO4 and the crude product was purified
by column chromatography (ethyl acetate/hexane, 2:8) to afford al-
kynol 10 (3.59 g, 95%) as a liquid. [α]2D5 = –1.4 (c = 1.8, CHCl3).
1H NMR (200 MHz, CDCl3): δ = 7.34–7.17 (m, 5 H, PhH), 4.47
(s, 2 H, OCH2Ph), 4.29 (t, J = 5.5 Hz, 1 H, CHOH-alkyne), 3.43
(t, J = 6.2 Hz, 2 H, CH2OBn), 2.37 (d, J = 2.3 Hz, 1 H, alkyne-
H), 1.95–1.21 (m, 10 H, (CH2)5) ppm. 13C NMR (75 MHz, CDCl3):
δ = 138.2, 128.0, 127.4, 127.3, 85.1, 72.5, 72.3, 70.0, 61.6, 37.3,
29.0, 26.0 ppm. IR (neat): ν = 3426, 2927, 2854, 1456, 1095, 736,
˜
697 cm–1. HRMS (ESI): calcd. for C16H24O2Na [M + Na]+
271.1673; found 271.1666.
(2S,3S)-3-[6-(Benzyloxy)hexyl]oxiran-2-ylmethanol (9): Anhydrous
CH2Cl2 (50 mL) was added to activated molecular sieves powder
(4 Å, 2.3 g) and the suspension was cooled to –20 °C under an N2
atmosphere. l-(+)-DIPT (0.9 mL, 4.2 mmol) and Ti(OiPr)4
(1.3 mL, 4.2 mmol) were added with stirring and the resulting mix-
ture was stirred for 30 min at –20 °C. The allyl alcohol 8a (5.2 g,
21.0 mmol) in anhydrous CH2Cl2 (6 mL) was added and the re-
sulting mixture was stirred for another 30 min at –20 °C. tButyl
hydroperoxide (TBHP; 5.8 m in toluene, 14.4 mL, 41.9 mmol) was
then added and the resulting mixture was stirred at the same tem-
perature for 8 h, then warmed to 0 °C. Upon completion of the
reaction (monitored by TLC), the reaction mixture was quenched
with water (25 mL) and stirred at r.t. for 2 h. Aqueous NaOH
(30%), saturated with NaCl (8 mL) was then added and the re-
sulting mixture was stirred vigorously at r.t. for a further 30 min.
The resulting mixture was filtered through a Celite pad and the
filter cake washed well with CH2Cl2. The organic phase was sepa-
rated and the aqueous phase was extracted with CH2Cl2
(2ϫ50 mL). The combined organic layers were washed with brine
and dried with Na2SO4. Removal of the solvent under reduced
pressure and purification by flash column chromatography (ethyl
acetate/hexane, 3:7) afforded 9 (5.03 g, 91%) as a colorless viscous
liquid. [α]2D5 = –19.4 (c = 1.5, CHCl3). 1H NMR (200 MHz, CDCl3):
29.3, 28.8, 25.8, 24.7 ppm. IR (neat): ν = 3409, 2931, 2857, 1455,
˜
1097, 742, 697 cm–1. HRMS (ESI): calcd. for C16H22O2Na [M +
Na]+ 269.1517; found 269.1514.
(3S)-9-(Benzyloxy)-3-(2-bromo-1-ethoxyethoxy)-1-nonyne (10a): To
a stirred solution of alkynol 10 (3.58 g, 14.57 mmol) and NBS
(3.11 g, 17.48 mmol) in anhydrous CH2Cl2 (50 mL) under an N2
atmosphere at 0 °C, was added ethyl vinyl ether (3.3 mL,
34.96 mmol). The reaction mixture was then brought to r.t. and
stirred for 1 h. Upon completion of the reaction (monitored by
TLC), solvent was removed under reduced pressure and the residue
was purified by silica gel column chromatography (ethyl acetate/
hexane, 0.5:9.5) as quickly as possible to obtain the bromo acetal
1
10a (4.77 g, 83%) as a colorless oil. H NMR (200 MHz, CDCl3):
δ = 7.33–7.21 (m, 5 H, PhH), 4.95–4.76 (m, 1 H, OCHO-
Et(CH2Br)), 4.46 (s, 2 H, OCH2Ph), 4.37–4.21 (m, 1 H, CHOH-
alkyne), 3.83–3.27 (m, 6 H, OEt, CH2OBn and CH2Br), 2.39 (d, J
= 2.0 Hz, 1 H, alkyne-H), 1.80–1.18 (m, 13 H, (CH2)5 and
Me) ppm. IR (neat): ν = 2931, 2858, 1631, 1109, 1025, 751,
˜
δ = 7.37–7.17 (m, 5 H, PhH), 4.46 (s, 2 H, OCH2Ph), 3.83 (d, J = 695 cm–1. HRMS (ESI): calcd for C20H29BrO3Na [M + Na]+
13.3 Hz, 1 H, epoxy-CH2OH), 3.54 (d, J = 12.5 Hz, 1 H, epoxy-
CH2OH), 3.43 (t, J = 6.2 Hz, 2 H, CH2OBn), 2.93–2.81 (m, 2 H,
epoxy-H), 2.11 (br., 1 H, OH), 1.65–1.24 (m, 10 H, (CH2)5) ppm.
13C NMR (75 MHz, CDCl3): δ = 138.3, 128.0, 127.3, 127.2, 72.6,
419.1197; found 419.1203.
(2S)-2-[6-(Benzyloxy)hexyl]-5-ethoxy-3-methylenetetrahydrofuran
(11): nBu3SnH (4.8 mL, 18.0 mmol) was added dropwise to a solu-
tion of bromoacetal 10a (4.76 g, 12.05 mmol) heated to reflux in
anhydrous benzene (40 mL) with catalytic AIBN under an N2 at-
mosphere. The reduction was complete within 30 min as indicated
by TLC analysis. Benzene was removed under reduced pressure and
the crude residue was charged on a silica gel column, which was
first eluted first with petroleum ether to remove excess tri-nBu-tin
hydride and nBu3SnBr formed in the reaction. The product was
eluted with ethyl acetate/hexane (5%) to obtain the lactol ether 11
(3.45 g, 90%) as a colorless liquid. 1H NMR (200 MHz, CDCl3): δ
= 7.37–7.15 (m, 5 H, PhH), 5.12–5.03 (m, 1 H, C=CH2), 5.00–4.94
(m, 1 H, C=CH2), 4,86–4.81 (m, 1 H, OCHOEt), 4.47 (s, 2 H,
OCH2Ph), 4.44–4.24 (m, 1 H, CHOCHOEt), 3.80–3.64 (m, 1 H,
OEt), 3.48–3.35 (m, 3 H, OEt and CH2OBn), 2.83–2.42 (m, 2 H,
Allylic-CH2), 1.68–1.11 (m, 13 H, (CH2)5 and CH3) ppm. IR (neat):
70.0, 61.6, 58.4, 55.8, 31.2, 29.3, 28.9, 25.8, 25.6 ppm. IR (neat): ν
˜
= 3430, 2930, 2856, 1456, 1100, 737, 698 cm–1. HRMS (ESI): calcd.
for C16H24O3Na [M + Na]+ 287.1623; found 287.1622.
(2S,3R)-2-[6-(Benzyloxy)hexyl]-3-(chloromethyl)oxirane (9a): To a
stirred solution of triphenylphosphane (5.96 g, 22.8 mmol) in anhy-
drous CCl4 (50 mL), was added a solution of epoxy alcohol 9
(5.0 g, 18.9 mmol) in CCl4 (10 mL) followed by NaHCO3 (10 mol-
%). The reaction mixture was stirred at reflux temperature for 24 h.
After completion of the reaction (monitored by TLC), the mixture
was cooled to 30 °C and the solvent was removed under reduced
pressure. The crude product was purified by column chromatog-
raphy (ethyl acetate/hexane, 1:9) to afford epoxy chloride 9a
(4.77 g, 90%) as a colorless viscous liquid. [α]2D5 = –9.8 (c = 1.5,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 7.36–7.20 (m, 5 H, ν = 2928, 2856, 1631, 1454, 1382, 1096, 1024, 987, 757, 697 cm–1.
PhH), 4.45 (s, 2 H, OCH2Ph), 3.64–3.53 (m, 1 H, epoxy-CH2Cl),
˜
HRMS (ESI): calcd. for C20H30O3Na [M + Na]+ 341.2092; found
3.46–3.31 (m, 3 H, epoxy-CH2Cl and CH2OBn), 2.91 (td, J = 5.5, 341.2086.
2.1 Hz, 1 H, epoxy-H), 2.78 (td, J = 5.5, 2.1 Hz, 1 H, epoxy-H),
(S)-2-[6-(Benzyloxy)hexyl]-5-ethoxy-3-methyltetrahydrofuran (11a):
1.66–1.26 (m, 10 H, (CH2)5) ppm. 13C NMR (75 MHz, CDCl3): δ
Homoallylic lactol ether 11 (3.44 g, 10.82 mmol) and NiCl2·6H2O
(0.26 g, 10.80 mmol) were dissolved in MeOH (40 mL). The reac-
tion mixture was cooled to 0 °C and NaBH4 (0.82 g, 37.63 mmol)
was added in small portions (the solution turned black). After com-
plete addition, the reaction mixture was stirred at r.t. for 1 h. The
black precipitate formed was filtered and washed with MeOH and
the methanol was removed under reduced pressure. To the residual
= 138.6, 128.3, 127.5, 127.4, 72.8, 70.3, 59.0, 57.0, 44.7, 31.3, 29.6,
29.0, 26.0, 25.7 ppm. IR (neat): ν = 2929, 2855, 1455, 1101, 736,
˜
698 cm–1. HRMS (ESI): calcd. for C16H23O2NaCl [M + Na]+
305.1284; found 305.1272.
(3S)-9-(Benzyloxy)-1-nonyn-3-ol (10): A catalytic amount of ferric
nitrate was added to liquid ammonia (70 mL) at –78 °C, followed
700
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Amphidinin B and Analogues
solution, water (20 mL) was added and the solution was extracted
with diethyl ether (2ϫ30 mL). The combined organic layers were
washed with water (20 mL), brine (20 mL), dried with Na2SO4 and
concentration under reduced pressure. The crude product was puri-
fied by silica gel column chromatography (ethyl acetate/hexane, 1:9)
to afford a mixture of lactol ethers 11a (3.11 g, 90%) as a colorless
liquid. 1H NMR (200 MHz, CDCl3): δ = 7.32–7.19 (m, 5 H, PhH),
5.07–4.98 (m, 1 H, OCHOEt), 4.46 (s, 2 H, OCH2Ph), 3.96–3.60
(m, 2 H, OEt and CHOCHOEt), 3.48–3.28 (m, 3 H, OEt and
CH2OBn), 2.37–0.82 (m, 19 H, (CH2)6CHCH3 and (CH3)2) ppm.
(m, 1 H, OH), 2.42–2.14 (m, 1 H, CH2CHOH), 2.03–1.92 (m, 1 H,
CHCH3), 1.78–1.23 (m, 11 H, (CH2)5 and CH2CHOH), 1.04, 0.88
(2ϫd, J = 6.8, 7.5 Hz, 3 H) ppm. IR (neat): ν = 3412, 2931, 2857,
˜
1455, 1361, 1103, 987, 737, 697 cm–1. HRMS (ESI): calcd. for
C18H28NaO3 [M + Na]+ 315.1936; found 315.1928.
6-[(2S,3S,5S)-5-Allyl-3-methyltetrahydro-2-furanyl]-1-hexanol (13):
A solution of lactol 12a (1.26 g, 4.33 mmol) and allyltrimethylsilane
(2.1 mL, 13.01 mmol) in CH2Cl2 (20 mL) was cooled to –78 °C.
Freshly prepared 1 m solution of I2 (0.2 mL, 5 mol-%, 0.22 mmol)
in CH2Cl2 was added dropwise and the solution was stirred at
–78 °C for 1 h and slowly brought to ambient temperature after
completion of the allylation (monitored by TLC). An equivalent of
molecular iodine was added to the reaction mixture (1.3 g,
4.34 mmol) at 0 °C and stirred for additional 1 h at the same tem-
perature, then quenched with a saturated solution of Na2S2O3
(10 mL). The layers were separated and the organic phase was ex-
tracted with CH2Cl2 (3ϫ10 mL). The combined organic layers
were dried with Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(ethyl acetate/hexane, 1.5:8.5) to afford 13 (0.85 g, 87%) as a color-
less liquid (96:4 ratio determined by HPLC). [α]2D5 = +1.0 (c = 1.0,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 5.89–5.64 (m, 1 H,
CH=CH2), 5.11–4.97 (m, 2 H, CH=CH2), 4.00–4.14 (m, 1 H,
OCH-Allyl), 3.87–3.74 (m, 1 H, CHOCH-Allyl), 3.61 (t, J =
6.6 Hz, 2 H, CH2OH), 2.40–2.04 (m, 3 H, CH2CH-Allyl and
Allylic-CH2), 1.84–1.17 (m, 12 H, CH2CH-Allyl, CHCH3 and
(CH2)5), 0.90 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 134.8, 116.5, 81.3, 75.6, 62.6, 40.8, 39.1, 35.7, 32.4,
IR (neat): ν = 2932, 2855, 1454, 1369, 1109, 983, 737, 697 cm–1.
˜
HRMS (ESI): calcd. for C20H32NaO3 [M + Na]+ 343.2249; found
343.2247.
(4S,5S)-5-[6-(Benzyloxy)hexyl]-4-methyltetrahydrofuran-2-one (12-
syn) and (4R,5S)-5-[6-(Benzyloxy)hexyl]-4-methyltetrahydrofuran-2-
one (12-anti): Freshly prepared Jones reagent was added dropwise
to the solution of lactol ethers 11a (3.11 g, 9.73 mmol) in 2-propa-
nol-free acetone (20 mL) at 0 °C until the color of the reagent per-
sisted. The resulting mixture was then stirred at r.t. for 1 h. After
completion of the reaction (monitored by TLC), excess reagent was
quenched by the addition of 2-propanol and acetone was evapo-
rated. Water (20 mL) was added and the mixture was extracted
with diethyl ether (2ϫ20 mL). The combined organic layers were
washed with water (10 mL), brine (10 mL), dried with anhydrous
Na2SO4 and concentrated in vacuo. The crude product was purified
by flash column chromatography (ethyl acetate/hexane, 1:9) to af-
ford the syn-lactone 12-syn (2.0 g) and the anti-lactone 12-anti
(0.5 g) in 4:1 ratio as colorless liquids (2.5 g, 88%).
30.2, 29.4, 26.4, 25.5, 13.7 ppm. IR (neat): ν = 3410, 2930, 2858,
12-syn-Lactone: [α]2D5
= –31.5 (c =
1.4, CHCl3). 1H NMR
˜
1641, 1458, 1375, 1057, 996, 913, 758 cm–1. HRMS (ESI): calcd.
for C14H26NaO2 [M + Na]+ 249.1830; found 249.1829.
(300 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H, PhH), 4.46 (s, 2 H,
OCH2Ph), 4.41–4.31 (m, 1 H, CHOCOCH2), 3.42 (t, J = 6.5 Hz,
2 H, CH2OBn), 2.63 (dd, J = 16.6, 7.5 Hz, 1 H, CHOCOCH2),
2.57–2.47 (m, 1 H, CHCH3), 2.13 (dd, J = 16.6, 3.7 Hz, 1 H, CHO-
COCH2), 1.69–1.23 (m, 10 H, (CH2)5), 1.00 (d, J = 6.8 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.8, 138.6, 128.3,
127.5, 127.4, 83.5, 72.8, 70.2, 37.5, 32.9, 29.8, 29.6, 29.2, 26.0, 25.8,
6-[(2S,3S,5S)-5-Allyl-3-methyltetrahydrofuran-2-yl]hexanoic
Acid
(13a): To a vigorously stirred solution of alcohol 13 (0.69 g,
3.0 mmol) in CH3CN (6 mL) and H2O (3 mL) were added TEMPO
(95 mg, 0.61 mmol) and BAIB (2.45 g, 7.63 mmol). Stirring was
continued until TLC indicated complete conversion of the starting
material. The reaction mixture was quenched by the addition of
saturated Na2S2O3 (5 mL). The mixture was then extracted with
EtOAc (2ϫ30 mL) and the combined organic layers were dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography (ethyl
acetate/hexane, 3:7) to afford the pure acid 13a (697 mg, 95%) as
a colorless liquid. [α]2D5 = –4.8 (c = 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 5.90–5.63 (m, 1 H, CH=CH2), 5.09–4.97
(m, 2 H, CH=CH2), 4.01–4.15 (m, 1 H, OCH-Allyl), 3.87–3.76 (m,
1 H, CHOCH-Allyl), 2.40–2.05 (m, 6 H, CH2COOH, Allylic-CH2,
CH2CH-Allyl, and CHCH3), 1.85–1.21 (m, 9 H, CH2CH-Allyl and
(CH2)4), 0.89 (d, J = 7.3 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 179.5, 134.9, 116.8, 81.2, 76.0, 40.9, 39.1, 35.8, 34.0,
13.8 ppm. IR (neat): ν = 2930, 2855, 1774, 1631, 1456, 1384, 1161,
˜
1100, 931, 737, 698 cm–1. HRMS (ESI): calcd. for C18H26NaO3 [M
+ Na]+ 313.1779; found 313.1786.
12-anti-Lactone: [α]2D5 = –34.0 (c = 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.36–7.18 (m, 5 H, PhH), 4.46 (s, 2 H,
OCH2Ph), 3.98–3.90 (m, 1 H, CHOCOCH2), 3.43 (t, J = 6.5 Hz,
2 H, CH2OBn), 2.69–2.52 (m, 1 H, CHOCOCH2), 2.32–2.06 (m, 2
H, CHCH3 and CH2COOR), 1.70–1.23 (m, 9 H, CH2COOR and
(CH2)4), 1.13 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.6, 138.5, 128.3, 127.5, 127.4, 87.3, 72.8, 70.2, 37.0,
36.0, 33.9, 29.6, 29.1, 26.0, 25.6, 17.4 ppm.
(4S,5S)-5-[6-(Benzyloxy)hexyl]-4-methyltetrahydrofuran-2-ol (12a):
DIBAL-H (1.0 m in hexane, 5.5 mL, 5.5 mmol) was added to a
stirred solution of 12-syn-lactone (1.6 g, 5.5 mmol) in CH2Cl2
(60 mL) at –78 °C and the solution was stirred for 1 h at the same
temperature. After completion of the reaction (monitored by TLC),
the reaction mixture was quenched by addition of saturated potas-
sium sodium tartrate (6 mL) and allowed to warm to ambient tem-
perature. The aqueous phase was extracted with CH2Cl2
(2ϫ40 mL), and the combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (ethyl acetate/
hexane, 1.5:8.5) to afford lactol 12a (1.56 g, 95%) as a colorless oil.
30.0, 29.2, 26.1, 24.6, 13.9 ppm. IR (neat): ν = 3435, 2931, 2860,
˜
1709, 1459, 1226, 1091, 993, 913 cm–1. HRMS (ESI): calcd. for
C14H24NaO3 [M + Na]+ 263.1623; found 263.1619.
(4S)-3,6-[(2S,3S,5S)-5-Allyl-3-methyl-tetrahydrofuran-2-yl]-
hexanoyl-4-benzyl-1,3-oxazolan-2-one (14): To a stirred solution of
acid 13a (2.76 g, 11.48 mmol) in THF (40 mL) at –20 °C was added
Et3N (4.0 mL, 28.70 mmol) followed by pivaloyl chloride (1.4 mL,
11.48 mmol). After stirring for 1 h at –20 °C, LiCl (0.73 g,
17.22 mmol) followed by (S)-oxazolidinone (2.03 g, 11.48 mmol)
were added at the same temperature, and stirring was continued
1H NMR (300 MHz, CDCl3): δ = 7.36–7.17 (m, 5 H, PhH), 5.50– for 1 h at –20 °C and then for 2 h at 0 °C. After completion of the
5.32 (m, 1 H, OCHOH), 4.46 (s, 2 H, OCH2Ph), 4.12–3.79 (m, 1 reaction (monitored by TLC), the reaction mixture was quenched
H, CHOCHOH), 3.42 (t, J = 6.5 Hz, 2 H, CH2OBn), 3.22–2.93 with saturated NH4Cl (20 mL) and extracted with EtOAc
Eur. J. Org. Chem. 2011, 696–706
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J. S. Yadav et al.
FULL PAPER
(2ϫ40 mL). The combined organic layers were washed with brine
(40 mL), dried with anhydrous Na2SO4 and concentrated under re-
duced pressure. The crude product was purified by column
chromatography (ethyl acetate/hexane, 1.5:8.5) to afford 14 (3.90 g,
85%) as a colorless liquid. [α]2D5 = +34.3 (c = 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 7.37–7.14 (m, 5 H, PhH), 5.89–5.63 (m, 1
H, CH=CH2), 5.05 (d, J = 7.9, Hz, 1 H, CH=CH2), 4.98 (s, 1 H,
CH=CH2), 4.68–4.54 (m, 1 H, NCOOCH2), 4.22–3.99 (m, 2 H,
NCOOCH2, OCH-Allyl), 3.87–3.76 (m, 1 H, CHOCH-Allyl), 3.31
(dd, J = 3.5, 12.9 Hz, 1 H, NCHBn), 3.05–2.51 (m, 3 H, CH2Ph
and Allylic-CH2), 2.39–2.0 (m, 4 H, Allylic-CH2, CH2CON and
CHCH3), 1.84–1.20 (m, 10 H, (CH2)5), 0.90 (d, J = 7.1 Hz, 3 H,
CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 173.2, 153.3, 135.1,
134.9, 129.2, 128.8, 127.1, 116.6, 81.0, 75.8, 66.0, 55.0, 40.8, 39.1,
(75 MHz, CDCl3): δ = 134.9, 116.7, 81.3, 76.0, 68.2, 41.0, 39.2,
35.8, 35.6, 33.0, 30.3, 27.1, 26.8, 16.5, 13.9 ppm. IR (neat): ν =
˜
3410, 2930, 2858, 1642, 1458, 1375, 1057, 996, 913 cm–1. HRMS
(ESI): calcd. for C15H28NaO2 [M + Na]+ 263.1987; found 263.1980.
(S)-6-[(2S,3S,5S)-5-Allyl-3-methyltetrahydrofuran-2-yl]-2-methyl-
hexyloxy-(tert-butyl)dimethylsilane (15a): To a stirred solution of
alcohol 15 (3.9 g, 16.25 mmol) and imidazole (2.21 g, 32.5 mmol)
in CH2Cl2 (50 mL), was added tert-butyldimethylsilyl chloride
(TBDMSCl; 2.92 g, 19.50 mmol) at 0 °C portion-wise over a period
of 10 min. The reaction mixture was stirred at r.t. for 3 h. After
completion of the reaction (monitored by TLC), the mixture was
then diluted with CH2Cl2 (50 mL) and washed with water (10 mL),
brine (10 mL), and the organic layer was dried (Na2SO4) and con-
centrated in vacuo. The crude product was purified by flash
chromatography (ethyl acetate/hexane, 0.5:9.5) to afford TBS-pro-
tected alcohol 15a (5.465 g, 95%) as a colorless oil. [α]2D5 = –1.7 (c
37.8, 35.7, 35.3, 30.0, 29.1, 26.2, 24.0, 13.9 ppm. IR (neat): ν =
˜
2934, 2865, 1782, 1702, 1383, 1212, 1093, 704 cm–1. HRMS (ESI):
calcd. for C24H34NO4 [M + H]+ 400.2487; found 400.2472.
1
= 1.2, CHCl3). H NMR (200 MHz, CDCl3): δ = 5.90–5.65 (m, 1
(4S)-3-(2S)-6-[(2S,3S,5S)-5-Allyl-3-methyltetrahydrofuran-2-yl]-
2-methylhexanoyl-4-benzyl-1,3-oxazolan-2-one (14a): To a stirred
solution of 14 (1.94 g, 4.85 mmol) in anhydrous THF (20 mL) at
–78 °C, NaHMDS (1 m in THF, 7.28 mL, 7.28 mmol) was added
dropwise under a nitrogen atmosphere. After stirring for 30 min at
–78 °C, MeI (0.94 mL, 14.56 mmol) was added and the reaction
mixture was stirred for an additional 3 h at –78 °C. Upon comple-
tion of the reaction (monitored by TLC), the reaction mixture was
quenched with saturated NH4Cl (20 mL), warmed to r.t. and ex-
tracted with EtOAc (2ϫ50 mL). The combined organic extracts
were washed with brine (50 mL), dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography (ethyl acetate/hexane, 1.3:8.7) to
afford 14a (1.60 g, 80%) as a colorless liquid. [α]2D5 = +44.7 (c =
1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.15 (m, 5 H,
PhH), 5.86–5.67 (m, 1 H, CH=CH2), 5.08–4.97 (m, 2 H,
CH=CH2), 4.67–4.57 (m, 1 H, NCOOCH2), 4.22–4.0 (m, 2 H,
NCOOCH2, OCH-Allyl), 3.84–3.61 (m, 1 H, CHOCH-Allyl), 3.28
(dd, J = 3.0, 13.6 Hz, 1 H, NCHBn), 2.70 (dd, J = 9.8, 12.8 Hz, 1
H, CH2Ph), 2.34–2.09 (m, 3 H, CH2Ph, NCOCHCH3 and
CH2CH=CH2), 1.79–1.62 (m, 2 H, CH2CH=CH2 and CHCH3),
1.48–1.24 (m, 10 H, (CH2)5), 1.20 (d, J = 6.8 Hz, 3 H, CHCH3),
0.89 (d, J = 7.5 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 177.3, 152.9, 135.3, 135.0, 129.4, 128.9, 127.2, 116.7,
81.2, 75.9, 65.9, 55.3, 41.0, 39.2, 37.9, 37.6, 35.8, 33.3, 30.2, 27.4,
H, CH=CH2), 5.12–4.97 (m, 2 H, CH=CH2), 4.00–4.14 (m, 1 H,
OCH-Allyl), 3.86–3.76 (m, 1 H, CHOCH-Allyl), 3.47–3.28 (m, 2
H, CH2OTBS), 2.40–2.09 (m, 3 H, CHCH3 and Allylic-CH2), 1.83–
1.18 (m, 11 H, CHCH3 and (CH2)5), 0.93–0.83 (m, 15 H, OTBS
and 2ϫ CHCH3), 0.03 (s, 6 H, OTBS) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.0, 116.6, 81.4, 75.9, 68.4, 41.0, 39.3, 35.9, 35.7,
33.1, 30.4, 27.2, 26.9, 26.0, 18.3, 16.7, 14.0, –5.4 ppm. IR (neat): ν
˜
= 2930, 2858, 1642, 1458, 1375, 1057, 996, 913, 772 cm–1. HRMS
(ESI): calcd. for C21H42NaO2Si [M + Na]+ 377.2851; found
377.2838.
Compound 16: To a stirred solution of 15a (5.4 g, 15.25 mmol) in
THF (50 mL) and H2O (6 mL) was added OsO4 (106 mg,
0.76 mmol), and then NMO (1.96 g, 16.78 mmol) at r.t. The re-
sulting brown solution was stirred until TLC indicated complete
conversion of the starting material. The reaction mixture was di-
luted with diethyl ether (40 mL) and saturated NaHCO3 (20 mL)
was added. The organic layer was separated and the aqueous layer
was extracted with diethyl ether (2ϫ60 mL). The combined or-
ganic layers were washed with brine (50 mL), dried with Na2SO4
and concentrated under reduced pressure. The crude product was
used for the next step without further purification.
To a stirred solution of diol 15b in THF (20 mL), and H2O
(20 mL), was added NaIO4 (3.90 g, 18.30 mmol) at 23 °C under an
open atmosphere. After 1 h at the same temperature, the resulting
reaction mixture was diluted with diethyl ether (20 mL) and H2O
(20 mL). The layers were separated and the aqueous layer was ex-
tracted with diethyl ether (2ϫ50 mL). The combined organic layers
were washed with H2O (50 mL), brine (50 mL), dried with anhy-
drous Na2SO4 and concentrated under reduced pressure. The crude
aldehyde was purified by flash chromatography (ethyl acetate/hex-
ane, 1:9) to afford compound 16 (4.10 g, 76%) as a colorless oil.
[α]2D5 = –3.5 (c = 1.6, CHCl3). 1H NMR (200 MHz, CDCl3): δ =
9.78 (s, 1 H, CHO), 4.57–4.40 (m, 1 H, OCHCH2CHO), 3.91–3.79
(m, 1 H, CHOCHCH2CHO), 3.48–3.29 (m, 2 H, CH2OTBS), 2.70–
2.41 (m, 2 H, CH2CHO), 2.38–2.16 (m, 1 H, CHCH3), 1.94–1.66
(m, 2 H, CH2CHCH2CHO), 1.64–0.98 (m, 9 H, CHCH3 and
(CH2)4), 0.96–0.83 (m, 15 H, OTBS and 2ϫCH3), 0.02 (s, 6 H,
OTBS) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.6, 81.7, 71.6,
68.5, 50.5, 40.0, 35.7, 35.8, 33.1, 30.3, 27.2, 26.8, 25.9, 18.4, 16.7,
26.6, 17.3, 14.0 ppm. IR (neat): ν = 2933, 2862, 1783, 1701, 1385,
˜
1211, 1095, 703 cm–1. HRMS (ESI): calcd. for C25H35NO4Na [M
+ Na]+ 436.2463; found 436.2465.
(2S)-6-[(2S,3S,5S)-5-Allyl-3-methyltetrahydrofuran-2-yl]-2-methyl-
hexan-1-ol (15): To a solution of compound 14a (1.6 g, 3.87 mmol)
in anhydrous diethyl ether (20 mL) at 0 °C, was added one drop of
distilled water followed portion-wise by LiBH4 (0.17 g, 7.74 mmol),
and stirring was continued until TLC analysis indicated complete
conversion of the starting material. The reaction was quenched
with saturated aqueous NH4Cl (20 mL) and extracted with diethyl
ether (2ϫ50 mL). The combined organic extract was washed with
brine (50 mL), dried with Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy (ethyl acetate/hexane, 1:4) to afford 15 (798 mg, 86%) as a
colorless liquid. [α]2D5 = –6.0 (c = 1.0, CHCl3). 1H NMR (200 MHz,
CDCl3): δ = 5.88–5.65 (m, 1 H, CH=CH2), 5.06 (d, J = 8.1 Hz, 1
H, CH=CH2), 4.99 (s, 1 H, CH=CH2), 4.01–4.15 (m, 1 H, OCH-
Allyl), 3.87–3.76 (m, 1 H, CHOCH-Allyl), 3.53–3.33 (m, 2 H,
CH2OH), 2.40–2.04 (m, 5 H, CH2CH-Allyl, CH2CH=CH2 and
13.8, –5.4 ppm. IR (neat): ν = 2930, 2858, 1729, 1458, 1375, 1057,
˜
996, 913, 772 cm–1. HRMS (ESI): calcd. for C20H40O3NaSi [M +
Na]+ 379.2644; found 379.2656.
Compound 16a: Sodium borohydride (424 mg, 11.23 mmol) was
CHCH3), 1.85–0.99 (m, 9 H, CHCH3, (CH2)4), 0.92 (d, J = 2.2 Hz, added portion-wise to a cooled solution (0 °C) of aldehyde 16
3 H, CHCH3), 0.89 (d, J = 2.2 Hz, 3 H, CHCH3) ppm. 13C NMR (4.0 g, 11.23 mmol) in MeOH (30 mL). The solution was stirred for
702
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Amphidinin B and Analogues
1 h at r.t., then the reaction was quenched by the addition of satu-
rated NH4Cl (10 mL) and methanol was concentrated. The aque-
ous phase was extracted with EtOAc (2ϫ50 mL) and the combined
organic layers were washed with brine (50 mL), dried with Na2SO4
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (ethyl acetate/hexane, 2:8) to af-
ford alcohol 16a (3.82 g, 95%) as a colorless oil. [α]2D5 = –7.4 (c =
1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 4.32–4.20 (m, 1 H,
1:9) to afford compound 17a (2.83 g, 93%) as a colorless oil. [α]2D5
= –12.9 (c = 1.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.26
1
(d, J = 8.7 Hz, 2 H, CH3OC6H4), 6.87 (d, J = 8.7 Hz, 2 H,
CH3OC6H4), 4.40 (ABq, J = 11.5, 15.1 Hz, 2 H, OCH2C6H4-
OCH3), 4.22–4.11 (m, 1 H, OCHCH2CH2OPMB), 3.85–3.77 (m, 4
H, OCH3 and CHOCHCH2CH2OPMB), 3.59–3.37 (m, 4 H,
CH2OPMB and CH2OH), 2.27–2.14 (m, 1 H, CHCH3), 1.91–1.05
(m, 13 H, (CH2)6 and CHCH3), 0.93–0.87 (m, 6 H, 2ϫCH3) ppm.
OCHCH2 CH2 OH), 3. 93–3. 73 (m, 3 H, CH2 OTBS and 13C NMR (75 MHz, CDCl3): δ = 159.0, 130.5, 129.1, 113.6, 80.9,
CHOCHCH2CH2OH), 3.43 (dd, J = 9.8, 5.8 Hz, 1 H, CH2OH), 73.8, 72.5, 68.0, 67.5, 55.1, 40.0, 36.7, 35.7, 35.6, 33.0, 30.2, 27.0,
3.34 (dd, J = 9.8, 6.6 Hz, 1 H, CH2OH), 3.2 (br. s, 1 H, OH), 2.28–
2.15 (m, 1 H, CHCH3), 1.83–1.20 (m, 12 H, CHCH3, CH2CH2OH
and (CH2)5), 1.12–0.98 (m, 1 H, CH2CH2OH), 0.91–0.83 (m, 15 H,
OTBS and 2 ϫ CH3), 0.03 (s, 6 H, OTBS) ppm. 13C NMR
(75 MHz, CDCl3): δ = 81.4, 77.2, 68.4, 62.0, 40.5, 38.0, 35.7, 35.6,
26.8, 16.5, 13.9 ppm. IR (neat): ν = 3436, 2932, 2860, 1613, 1513,
˜
1460, 1247, 1091, 1037, 821, 756 cm–1. HRMS (ESI): calcd. for
C22H36NaO4 [M + Na]+ 387.2511; found 387.2519.
(S)-6-{(2S,3S,5R)-5-[2-(4-Methoxybenzyloxy)ethyl]-3-methyltetra-
hydrofuran-2-yl}-2-methylhexanoic Acid (4): To a vigorously stirred
solution of alcohol 17a (2.8 g, 7.69 mmol) in CH2Cl2 (15 mL) and
H2O (7 mL), was added TEMPO (0.24 g, 1.54 mmol) and BAIB
(6.2 g, 19.23 mmol). Stirring was continued until TLC indicated
complete conversion of the starting material. The reaction mixture
was quenched by the addition of saturated Na2S2O3 (50 mL), the
mixture was extracted with EtOAc (2ϫ100 mL) and the combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (ethyl acetate/hexane, 1:4) to afford the pure acid
4 (2.76 g, 95%) as a colorless liquid. [α]2D5 = –2.1 (c = 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.7 Hz, 2 H,
CH3OC6H4), 6.87 (d, J = 8.7 Hz, 2 H, CH3OC6H4), 4.43 (ABq, J
= 11.5, 3.6 Hz, 2 H, OCH2C6H4OCH3), 4.22–4.11 (m, 1 H,
OCHCH 2 CH2 O P MB ), 3 . 8 5 – 3 . 7 7 ( m , 4 H , O C H 3 a n d
CHOCHCH2CH2OPMB), 3.54 (t, J = 6.6 Hz, 2 H, CH2OPMB),
2.52–2.37 (m, 1 H, CHCOOH), 2.27–2.14 (m, 1 H, CHCH3), 1.89–
1.62 (m, 3 H, CHCH2CH, CH2), 1.51–1.24 (m, 9 H, CHCH2CH,
(CH2)4), 1.17 (d, J = 7.0 Hz, 3 H, CH3), 0.88 (d, J = 7.1 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 182.3, 158.9, 130.4,
129.2, 113.6, 80.8, 73.8, 72.5, 67.3, 55.2, 39.9, 39.4, 36.6, 35.6, 33.5,
33.0, 30.4, 27.2, 26.9, 25.9, 18.3, 16.7, 14.0, –5.4 ppm. IR (neat): ν
˜
= 3426, 2857, 1465, 1253, 1093, 839, 775 cm–1. HRMS (ESI): calcd.
for C20H42NaO3Si [M + Na]+ 381.2800; found 381.2805.
((S)-6-{(2S,3S,5R)-5-[2-(4-Methoxybenzyloxy)ethyl]-3-methyltetra-
hydrofuran-2-yl}-2-methylhexyloxy)(tert-butyl)dimethylsilane (17):
To a stirred suspension of NaH (60%, 0.61 g, 15.92 mmol) in THF
(20 mL) was added a solution of mono-protected alcohol 16a
(3.80 g, 10.61 mmol) in anhydrous THF (20 mL) dropwise over a
period of 10 min at 0 °C. The reaction mixture was stirred at r.t.
for 1 h, then freshly prepared p-methoxybenzyl bromide (3.2 g,
15.92 mmol) dissolved in THF (10 mL) was added at 0 °C over a
period of 10 min, followed by addition of TBAI (0.195 g,
0.53 mmol) and the reaction mixture was stirred at r.t. until TLC
indicated complete conversion of the starting material. The reac-
tion mixture was quenched by addition of cold water (10 mL) and
THF was removed under reduced pressure. The crude mixture was
extracted with ethyl acetate (2ϫ20 mL) and the combined organic
layer was washed with brine (10 mL) and dried with anhydrous
Na2SO4. Concentration under reduced pressure and purification
by silica gel column chromatography (ethyl acetate/hexane, 0.5:9.5)
afforded p-methoxybenzyl ether 17 (4.05 g, 80%) as a colorless li-
30.0, 27.2, 26.3, 16.8, 13.8 ppm. IR (neat): ν = 2924, 2854, 1695,
˜
1
quid. [α]2D5 = –7.8 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3):
1513, 1460, 1247, 1091, 1037, 821, 756 cm–1. HRMS (ESI): calcd.
for C22H34NaO5 [M + Na]+ 401.2304; found 401.2315.
δ = 7.26 (d, J = 8.8 Hz, 2 H, CH3OC6H4), 6.86 (d, J = 8.8 Hz, 2
H, CH3OC6H4), 4.49–4.38 (m, 2 H, OCH2C6H4OCH3), 4.22–4.10
(m, 1 H, OCHCH2CH2OPMB), 3.80 (s, 3 H, OCH3), 3.58–3.51 (m,
2 H, CH2OPMB and CHOCHCH2CH2OPMB), 3.44 (dd, J = 9.8,
5.8 Hz, 1 H, CH2OTBS), 3.34 (dd, J = 9.8, 6.6 Hz, 1 H,
CH2OTBS), 2.25–2.15 (m, 1 H, CHCH3), 1.92–1.66 (m, 3 H,
CHCH3 and CH2CHCH2CH2OPMB), 1.63–1.21 (m, 10 H,
CH2CH2OPMB and (CH2)4), 1.11–0.96 (m, 1 H, CH2CH2OTBS),
0.92–0.84 (m, 15 H, OTBS and 2ϫCH3), 0.03 (s, 6 H, OTBS) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.0, 129.4, 129.2, 113.7, 80.9,
73.9, 72.6, 68.4, 67.6, 55.2, 40.1, 36.9, 35.8, 35.7, 33.1, 30.4, 27.2,
1-[((S)-3-Iodo-2-methylpropoxy)methyl]benzene (7a): To a stirred
solution of mono-benzyl ether 7 (20.0 g, 111.1 mmol) in a mixture
of anhydrous diethyl ether (150 mL) and anhydrous CH3CN
(50 mL), was added triphenylphosphane (TPP; 57.99 g,
222.2 mmol), imidazole (22.69 g, 333.3 mmol), and iodine (56.44 g,
222.2 mmol) at 0 °C. The resulting mixture was stirred at r.t. for
1 h. After completion of the reaction (monitored by TLC), the re-
action mixture was diluted with hexane and the solid material was
filtered and washed with ethyl acetate/hexane (10%). The filtrate
was concentrated under reduced pressure and the crude product
was dissolved in diethyl ether (100 mL) and washed with aqueous
sodium thiosulphate (10%, 75 mL), brine (75 mL) and dried with
Na2SO4. Concentration under reduced pressure and purification
by silica gel column chromatography (ethyl acetate/hexane, 0.3:9.7)
afforded the iodo-compound 7a (29 g, 90%) as a viscous liquid.
[α]2D5 = +8.2 (c = 1.5, CHCl3). 1H NMR (200 MHz, CDCl3): δ =
7.35–7.20 (m, 5 H, C6H5), 4.48 (s, 2 H, OCH2Ph), 3.42–3.19 (m, 4
H, CH2OBn and CH2I), 1.84–1.65 (m, 1 H, CHCH3), 0.99 (d, J =
6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.2,
26.9, 25.9, 18.3, 16.7, 13.9, –5.37 ppm. IR (neat): ν = 2930, 2856,
˜
1612, 1513, 1463, 1248, 1093, 1037, 838, 775 cm–1. HRMS (ESI):
calcd. for C28H50NaO4Si [M + Na]+ 501.3376; found 501.3383.
(S)-6-{(2S,3S,5R)-5-[2-(4-Methoxybenzyloxy)ethyl]-3-methyltetra-
hydrofuran-2-yl}-2-methylhexan-1-ol (17a): To a solution of com-
pound 17 (4.0 g, 8.37 mmol) in THF (30 mL), was added 70 %
HF·Py complex (4.96 mL, 10.87 mmol) at r.t. The reaction mixture
was stirred until TLC indicated complete conversion of the starting
material. The reaction mixture was then quenched with ice-water
(6 mL) and the resulting mixture was diluted with diethyl ether
(30 mL). The organic layer was separated and the aqueous layer
was extracted with diethyl ether (2ϫ50 mL). The combined or-
ganic layers were successively washed with water (50 mL) and brine
(50 mL), dried with anhydrous Na2SO4 and concentrated. The resi-
due was purified by flash chromatography (ethyl acetate/hexane,
128.2, 127.3, 73.9, 73.0, 35.0, 17.5, 13.7 ppm. IR (neat): ν = 2858,
˜
1642, 1454, 1099, 739, 697 cm–1. HRMS (ESI): calcd. for C11H15-
INaO [M + Na]+ 313.0065; found 313.0059.
(R)-5-(Benzyloxy)-4-methyl-2-methylenepentan-1-ol (18): To a
stirred solution of diethyl malonate (14.65 mL, 96.55 mmol) in an-
Eur. J. Org. Chem. 2011, 696–706
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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703

J. S. Yadav et al.
FULL PAPER
hydrous THF (100 mL) was added nBuLi (1.6 m in hexane),
60.34 mL, 96.55 mmol) at 0 °C. After 15 min, iodo-compound 7a
(28.0 g, 96.55 mmol) in anhydrous THF (50 mL) was added to the
reaction mixture over a period of 10 min. The resulting mixture
was stirred at r.t. for 4 h. After completion of the reaction (moni-
tored by TLC), nBuLi (1.6 m in hexane), 60.34 mL, 96.55 mmol)
was added at 0 °C. After 15 min the reaction mixture was transfer-
red by using a cannula into a separately generated alane complex
[To a stirred suspension of LiAlH4 (11.0 g, 289.65 mmol) in anhy-
drous THF (200 mL) at 0 °C under an N2 atmosphere, was added
dropwise a solution of AlCl3 (12.87 g, 96.55 mmol) in THF
(100 mL)]. The reaction mixture was stirred at reflux temperature
for 6 h. After completion (reaction monitored by TLC), the reac-
tion mixture was quenched by the addition of crushed ice, filtered
through Celite and washed with hot ethyl acetate. The combined
organic layers were dried with anhydrous Na2SO4 and concentrated
under reduced pressure. Purification of the crude product by silica
gel column chromatography (ethyl acetate/hexane, 1:9) afforded al-
lyl alcohol 18 (12.76 g, 60%) as a viscous liquid. [α]2D5 = –0.6 (c =
1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H,
C6H5), 5.09 (s, 1 H, C=CH2), 4.81 (s, 1 H, C=CH2), 4.45 (s, 2 H,
OCH2Ph), 3.97 (s, 2 H, CH2=CCH2OH), 3.27 (d, J = 6.0 Hz, 2 H,
CH2OBn), 2.25 (dd, J = 13.6, 6.0 Hz, 1 H, CH2=CCH2), 2.13 (br.
s, 1 H, OH), 2.02–1.79 (m, 2 H, CH2=CCH2 and CHCH3), 0.91
(d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
147.1, 138.3, 128.2, 127.4, 127.4, 110.7, 75.4, 72.9, 65.4, 37.5, 31.7,
dried with Na2SO4, and concentrated under reduced pressure. Puri-
fication of the crude product by silica gel column chromatography
(ethyl acetate/hexane, 0.8:9.2) afforded the homoallylic alcohol 19
1
(14.31 g, 76%) as a colorless liquid. H NMR (200 MHz, CDCl3):
δ = 7.34–7.21 (m, 5 H, C6H5), 4.86 (d, J = 3.0 Hz, 2 H, C=CH2),
4.46 (d, J = 3.0 Hz, 2 H, OCH2Ph), 3.74–3.60 (m, 1 H, CHOH),
3.31–3.21 (m, 2 H, CH2OBn), 2.34–2.13 (m, 2 H, CH2=CCH2),
2.08–1.72 (m, 3 H, CHCH3 and CH2=CCH2), 1.64 (br. s, 1 H, OH),
1.55–1.29 (m, 4 H, (CH2)2), 0.97–0.88 (m, 6 H, 2ϫCH3) ppm. IR
(neat): ν = 3453, 2957, 2927, 2868, 1641, 1455, 1207, 1095, 737,
˜
697 cm–1. HRMS (ESI): calcd. for C18H28NaO2 [M + Na]+
299.1987; found 299.1989.
(4S,8R)-9-(Benzyloxy)-8-methyl-6-methylenenonan-4-ol (20) and
(4S,8R)-9-(Benzyloxy)-8-methyl-6-methylenenon-an-4-yl Acetate
(21): To a solution of homoallylic alcohol 19 (14.3 g, 51.73 mmol)
in diisopropyl ether (600 mL) was added vinyl acetate (13.5 mL,
155.19 mmol) and Lipase PS-C “Amano” II (2.59 g, or 0.1 mmol
of alcohol, 5 mg enzyme) at r.t. After stirring for 4 d at r.t., the
mixture was filtered through Celite and the filtrate was concen-
trated under reduced pressure. The crude product was purified by
silica gel column chromatography (ethyl acetate/hexane, 0.5:9.5) to
obtain the homoallylic acetate 21 (6.26 g, 38%; Ͼ98% ee) as a col-
orless liquid [the enantiomeric excess ee was measured by chiral
HPLC using CHIRAL PAK-IC column. Eluent: hexane/IPA, 99:1;
flow rate: 1.0 mL/min; 25 °C (λmax = 210 nm)]. The unrequired
alcohol 20 was converted into the required acetate 21 by an oxi-
dation, reduction, followed by enzymatic resolution sequence.
17.0 ppm. IR (neat): ν = 3425, 2923, 2860, 1647, 1454, 1094, 739,
˜
697 cm–1. HRMS (ESI): calcd. for C14H20NaO2 [M + Na]+
243.1361; found 243.1368.
Compound 21: [α]2D5 = +7.8 (c = 1.5, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 7.31–7.17 (m, 5 H, C6H5), 5.03–4.93 (m, 1 H,
CHOAc), 4.77 (s, 2 H, C=CH2), 4.47 (s, 2 H, OCH2Ph), 3.33–3.19
(m, 2 H, CH2OBn), 2.29–2.10 (m, 3 H, CH2=CCH2), 1.98 (s, 3 H,
OAc), 1.87–1.76 (m, 1 H, CH2=CCH2), 1.54–1.41 (m, 3 H, CHCH3
and CH2), 1.39–1.23 (m, 2 H, CH2), 0.95–0.87 (m, 6 H,
2 ϫ CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.7, 143.9,
138.6, 128.2, 127.5, 127.4, 113.6, 75.4, 72.9, 72.2, 40.6, 40.4, 36.1,
1-{[(R)-4-(Bromomethyl)-2-methylpent-4-enyloxy]methyl}benzene
(18a): To a solution of CBr4 (19.16 g, 57.72 mmol) in anhydrous
CH2Cl2 (100 mL) under a nitrogen atmosphere, was added a solu-
tion of TPP (30.13 g, 115.44 mmol) in anhydrous CH2Cl2 (100 mL)
dropwise over a period of 30 min at 0 °C. The mixture was stirred
for 30 min at 0 °C followed by the addition of allylic alcohol 18
(12.7 g, 57.72 mmol) and imidazole (7.4 g, 115.44 mmol) in anhy-
drous CH2Cl2 (50 mL). The reaction mixture was allowed to warm
to r.t., then the solvent was evaporated to a small volume and hex-
ane was added to the reaction mixture. The resultant precipitate
was filtered and washed with ethyl acetate/hexane (10%). The fil-
trate was concentrated under reduced pressure and the crude prod-
uct was purified by silica gel column chromatography (ethyl acet-
ate/hexane, 0.5:9.5) to afford 18a (14.71 g, 90%) as a colorless li-
31.4, 21.2, 18.6, 17.1, 13.9 ppm. IR (neat): ν = 2959, 2929, 2870,
˜
1737, 1456, 1371, 1241, 1096, 1022, 898, 738, 698 cm–1. HRMS
(ESI): calcd. for C20H30NaO3 [M + Na]+ 341.2093; found 341.2097.
(4R,8R)-9-(Benzyloxy)-8-methyl-6-methylenenonan-4-ol (5): To a
stirred solution of (R)-homoallylic ester 21 (6.2 g, 19.47 mmol) in
MeOH (40 mL) was added Na metal (672 mg, 29.2 mmol) portion-
wise at 0 °C over a period of 10 min. The reaction mixture was
stirred at r.t. for 1 h. After completion of the reaction (monitored
by TLC), the reaction mixture was concentrated under reduced
pressure. The crude product was dissolved in H2O (30 mL) and
extracted with diethyl ether (2ϫ 50 mL). The combined organic
layer was washed with brine (50 mL), dried with Na2SO4, and puri-
fied by silica gel column chromatography (ethyl acetate/hexane,
0.8:9.2) to afford (R)-homoallylic alcohol 5 (5.10 g, 95%) as a col-
1
quid. [α]2D5 = –2.0 (c = 2.0, CHCl3). H NMR (200 MHz, CDCl3):
δ = 7.34–7.24 (m, 5 H, C6H5), 5.19 (s, 1 H, C=CH2), 4.93 (s, 1 H,
C=CH2), 4.47 (s, 2 H, OCH2Ph), 3.92 (s, 2 H, CH2=CCH2Br), 3.28
(dd, J = 2.2, 5.1 Hz, 2 H, CH2 OBn), 2.49–2.32 (m, 1 H,
CH2=CCH2), 2.08–1.91 (m, 2 H, CH2=CCH2 and CHCH3), 0.94
(d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
148.8, 138.6, 128.3, 127.5, 127.4, 116.5, 75.3, 73.0, 37.8, 36.6, 31.5,
1
orless liquid. [α]2D5 = +0.6 (c = 1.2, CHCl3). H NMR (300 MHz,
17.0 ppm. IR (neat): ν = 2923, 2855, 1638, 1455, 1207, 1111, 740,
˜
696, 541 cm–1. HRMS (ESI): calcd. for C14H19BrNaO [M + Na]+
305.0517; found 305.0520.
CDCl3): δ = 7.33–7.21 (m, 5 H, C6H5), 4.85 (s, 2 H, C=CH2), 4.46
(s, 2 H, OCH2Ph), 3.72–3.63 (m, 1 H, CHOH), 3.31–3.21 (m, 2 H,
CH2OBn), 2.24–2.14 (m, 2 H, CH2=CCH2), 2.07–1.80 (m, 3 H,
CHCH3 and CH2=CCH2), 1.63 (br. s, 1 H, OH), 1.56–1.31 (m, 4
H, (CH2)2), 0.96–0.90 (m, 6 H, 2ϫCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 145.0, 138.6, 128.3, 127.5, 127.4, 113.6, 75.3, 73.0,
(R)-8-[(Benzyloxy)methyl]-6-methylenenonan-4-ol (19): To a stirred
mixture of activated Zn (33.65 g, 517.73 mmol) in THF (100 mL),
was added 18a (14.60 g, 51.77 mmol) in THF (50 mL) dropwise.
After stirring for 1 h, butanal (13.9 mL, 155.32 mmol) was added
and the reaction mixture was stirred for an additional 3 h at r.t.
then quenched by addition of saturated aqueous NH4Cl (100 mL).
After 30 min, the reaction mixture was filtered to remove the excess
zinc. The filtrate was acidified with 10% HCl (50 mL) and the or-
ganic layer was separated. The aqueous layer was extracted with
diethyl ether (2 ϫ100 mL), the combined organic extracts were
68.7, 44.3, 40.5, 39.2, 31.7, 18.9, 17.4, 14.1 ppm. IR (neat): ν =
˜
3435, 2957, 2927, 2868, 1641, 1455, 1365, 1095, 1022, 895, 737,
697 cm–1. HRMS (ESI): calcd. for C18H28NaO2 [M + Na]+
299.1987; found 299.1989.
(4R,8R)-9-(Benzyloxy)-8-methyl-6-methylenenonan-4-yloxy(tert-
butyl)dimethylsilane (24): To a stirred solution of (R)-homoallylic
704
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Eur. J. Org. Chem. 2011, 696–706

Amphidinin B and Analogues
alcohol 5 (2.6 g, 9.42 mmol) and imidazole (1.6 g, 23.55 mmol) in
CH2Cl2 (20 mL), was added a solution of TBDMS-Cl (1.69 g,
11.30 mmol) in CH2Cl2 (5 mL) at 0 °C over a period of 10 min.
The reaction mixture was stirred at r.t. for 3 h. Upon completion
of the reaction (monitored by TLC), the mixture was diluted with
CH2Cl2 (50 mL) and washed with water (40 mL) and brine
(40 mL). The organic layer was dried with Na2SO4 and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (ethyl acetate/hexane, 0.3:9.7) to afford TBS-
protected alcohol 24 (3.34 g, 91%) as a colorless oil. [α]2D5 = –1.4 (c
70.9, 43.8, 40.2, 39.0, 37.7, 25.9, 18.5, 18.1, 16.7, 14.2, –4.4,
–4.6 ppm. IR (neat): ν = 3423, 2956, 2930, 2858, 1709, 1463, 1252,
˜
1040, 834, 772 cm–1. HRMS (ESI): calcd. for C17H34O3NaSi [M +
Na]+ 337.2175; found 337.2185.
(2S)-(4R,8R)-9-(Benzyloxy)-8-methyl-6-methylenenonan-4-yl 6-
{(2S,3S,5R)-5-[2-(4-Methoxybenzyloxy)ethyl]tetrahydro-3-methyl-
furan-2-yl}-2-methylhexanoate (22): To a solution of acid 4 (2.70 g,
7.14 mmol) in toluene (25 mL) were added 2,4,6-trichlorobenzoyl
chloride (1.67 mL, 10.71 mmol) and diisopropylethylamine
(3.73 mL, 21.43 mmol). The mixture was stirred for 6 h at r.t., then
alcohol 5 (2.168 g, 7.85 mmol) in toluene (5 mL) was slowly added
to the mixture followed by addition of DMAP (1.3 g, 10.71 mmol)
in toluene (5 mL) at r.t. The reaction was stirred for an additional
3 h. Upon completion of the reaction (monitored by TLC), it was
quenched by addition of saturated aqueous NH4Cl (50 mL). The
aqueous phase was extracted with ethyl acetate (3ϫ50 mL) and
the combined extracts were washed with brine (30 mL), dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography (ethyl acet-
ate/hexane, 0.5:9.5) to afford compound 22 (3.86 g, 85%) as a col-
orless viscous liquid. [α]2D5 = +1.2 (c = 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.37–7.22 (m, 7 H, C6H5 and C6H4OCH3),
6.87 (d, J = 8.7 Hz, 2 H, C6H4OCH3), 5.08–4.97 (m, 1 H, CH-
(CH3)OCOR), 4.78 (d, J = 4.7 Hz, 2 H, C=CH2), 4.50 (s, 2 H,
OCH2Ph), 4.43 (ABq, J = 11.5, 3.7 Hz, 2 H, OCH2C6H4OCH3),
4.21–4.10 (m, 1 H, OCHCH2CH2OPMB), 3.86–3.75 (m, 4 H,
OCHCH(CH3) and OCH3), 3.54 (t, J = 7.3 Hz, 2 H, CH2OPMB),
3.38–3.32 (m, 1 H, CH2OBn), 3.27–3.20 (m, 1 H, CH2OBn), 2.44–
2.11 (m, 5 H, 2ϫAllylic-CH2 and CH(CH3)COOR), 2.08–1.81 (m,
2 H, CHCH3 and OCHCH2), 1.77–1.59 (m, 4 H, CHCH3,
OCHCH2CH2OPMB and OCHCH2CH(CH3)), 1.56–1.21 (m, 12
H, (CH2)6), 1.10 (d, J = 6.8 Hz, 3 H, CHCH3), 0.95–0.86 (m, 9 H,
2 ϫ CHCH3, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
176.2, 158.9, 143.6, 138.5, 130.4, 129.0, 128.0, 127.2, 127.1, 113.5,
113.4, 80.6, 75.2, 73.7, 72.7, 72.4, 71.3, 67.4, 55.0, 40.6, 40.1, 40.0,
39.6, 36.7, 36.0, 35.6, 33.6, 31.2, 30.1, 27.3, 26.3, 18.4, 17.0,
1
= 1.5, CHCl3). H NMR (200 MHz, CDCl3): δ = 7.34–7.24 (m, 5
H, C6H5), 4.76 (d, J = 2.2 Hz, 2 H, C=CH2), 4.48 (s, 2 H,
OCH2Ph), 3.85–3.71 (m, 1 H, CHOTBS), 3.27 (d, J = 5.8 Hz, 2 H,
CH2OBn), 2.30–1.59 (m, 5 H, 2ϫCH2=CCH2 and CHCH3), 1.51–
1.14 (m, 4 H, (CH2)2), 0.96–0.85 (m, 15 H, OTBS and 2ϫCH3),
0.04 (s, 6 H, OTBS) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.9,
138.8, 128.3, 127.4, 127.4, 113.3, 75.6, 72.9, 70.8, 43.9, 40.8, 39.0,
31.6, 26.0, 18.5, 18.1, 17.0, 14.2, –4.4, –4.5 ppm. IR (neat): ν =
˜
2930, 2856, 1641, 1462, 1365, 1250, 1101, 1035, 830, 770, 735,
693 cm–1. HRMS (ESI): calcd. for C24H42NaO2Si [M + Na]+
413.2852; found 413.2845.
Compound 24a: To a stirred solution of naphthalene (4.33 g,
33.84 mmol) in THF (30 mL) was added lithium metal (177 mg,
25.38 mmol) in small pieces at r.t. The reaction mixture was stirred
at r.t. under an argon atmosphere until the lithium metal was com-
pletely dissolved (3 h). The resulting dark-green solution of lithium
naphthalenide was cooled to –20 °C and compound 24 (3.3 g,
8.46 mmol) in THF (6 mL) was added dropwise over 5 min. The
resulting mixture was stirred at –20 °C for 30 min. After comple-
tion of the reaction (monitored by TLC), the reaction mixture was
quenched with aqueous ammonium chloride (6 mL). The resulting
solution was extracted with diethyl ether (2ϫ60 mL) and the com-
bined extracts were washed with water and brine (10 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was purified by column chromatography (ethyl acetate/
hexane, 0.9:9.1) to afford 24a (2.41 g, 95%) as a colorless liquid.
1
[α]2D5 = +15.5 (c = 1.2, CHCl3). H NMR (200 MHz, CDCl3): δ =
13.8 ppm. IR (neat): ν = 2933, 2861, 1727, 1613, 1513, 1458, 1374,
˜
4.79 (s, 2 H, C=CH2), 3.85–3.69 (m, 1 H, CHOTBS), 3.45 (d, J =
5.3 Hz, 2 H, CH2OH), 2.25–2.03 (m, 4 H, 2ϫCH2=CCH2), 1.91–
1.71 (m, 1 H, CHCH3), 1.49–1.17 (m, 4 H, (CH2)2), 1.01–0.76 (m,
15 H, OTBS and 2ϫCH3), 0.04 (s, 6 H, OTBS) ppm. 13C NMR
(75 MHz, CDCl3): δ = 145.4, 113.4, 70.9, 68.2, 43.7, 40.7, 39.0,
1248, 1174, 1095, 1035, 899, 822, 739, 698 cm–1. HRMS (ESI):
calcd. for C40H60NaO6 [M + Na]+ 659.4287; found 659.4282.
(2S)-(4R,8R)-9-Hydroxy-8-methyl-6-methylenenonan-4-yl 6-
[(2S,3S,5R)-Tetrahydro-5-(2-hydroxyethyl)-3-methylfuran-2-yl]-2-
methylhexanoate (3): DDQ (40.5 g, 179.24 mmol) was added to a
solution of ester 22 (3.8 g, 5.97 mmol) in CH2Cl2/H2O (590 mL,
10:1 v/v). The reaction mixture was stirred for 18 h at r.t. and
quenched by addition of saturated aqueous NaHCO3 (400 mL).
The aqueous phase was extracted with diethyl ether (3ϫ100 mL)
33.8, 25.9, 18.5, 18.1, 16.7, 14.2, –4.4, –4.5 ppm. IR (neat): ν =
˜
3421, 2956, 2930, 2858, 1641, 1464, 1252, 1038, 833, 772 cm–1
.
HRMS (ESI): calcd. for C17H36O2NaSi [M + Na]+ 323.2382; found
323.2391.
Compound 25: To a vigorously stirred solution of alcohol 24a
(0.20 g, 0.66 mmol) in CH2Cl2 (6 mL) and H2O (3 mL) was added and the combined extracts were washed with saturated aqueous
TEMPO (21 mg, 0.13 mmol) and BAIB (536 mg, 1.66 mmol). Stir-
ring was continued until TLC indicated complete conversion of the
starting material. The reaction mixture was quenched by the ad-
dition of saturated Na2S2O3 (25 mL) and extracted with EtOAc
(2ϫ50 mL). The combined organic layers were dried with anhy-
drous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (ethyl acet-
ate/hexane, 1:4) to afford the pure acid 25 (190 mg, 93%) as a col-
NaHCO3 (100 mL) and brine (100 mL), dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash column chromatography (ethyl acetate/hexane,
4:6) to afford diol 3 (2.36 g, 93%) as a colorless oil. [α]2D5 = +11.4
(c = 1.3, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.03 (m, 1
H, CHOCOCHCH3), 4.80 (s, 2 H, C=CH2), 4.32–4.22 (m, 1 H,
OCHCH2CH2OH), 3.92–3.74 (m,
3
H, CH2CH2OH and
OCHCHCH3), 3.52–3.41 (m, 2 H, CH(CH3)CH2OH), 2.44–2.13
(m, 6 H, 2ϫAllylic-CH2, CH(CH3)COOR and OH), 1.92–1.59 (m,
orless liquid. [α]2D5 = +3.0 (c = 1.0, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 4.83 (s, 2 H, C=CH2), 3.83–3.73 (m, 1 H, CHOTBS), 7 H, (CH2)3 and CHCH3), 1.57–1.22 (m, 12 H, (CH2)6), 1.11 (d, J
2.73–2.60 (m, 1 H, CHCOOH), 2.46 (dd, J = 7.0, 14.4 Hz, 1 H,
CH2=CCH2), 2.23–2.05 (m, 3 H, 2ϫCH2=CCH2), 1.47–1.27 (m,
4 H, (CH2)2), 1.18 (d, J = 7.0 Hz, 3 H, CHCH3), 0.91–0.85 (m, 12
= 6.9 Hz, 3 H, CHCH3), 0.94–0.88 (m, 9 H, 2ϫCHCH3,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.8, 143.8,
113.5, 81.2, 76.9, 71.5, 67.5, 61.8, 41.0, 40.3, 39.7, 39.6, 38.0, 36.1,
H, CH2CH3 and OTBS), 0.05 (s, 3 H, OTBS), 0.04 (s, 3 H, 35.5, 33.6, 33.4, 30.1, 27.3, 26.5, 18.5, 17.2, 16.7, 13.9, 13.8 ppm.
OTBS) ppm. 13C NMR (75 MHz, CDCl3): δ = 182.0, 146.7, 114.0,
IR (neat): ν = 3404, 2928, 2860, 1727, 1458, 1379, 1177, 1043,
˜
Eur. J. Org. Chem. 2011, 696–706
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
705

J. S. Yadav et al.
FULL PAPER
897 cm–1. HRMS (ESI): calcd. for C25H46NaO5 [M + Na]+
449.3242; found 449.3259.
lowships. We are thankful to Prof. J. Kobayashi for providing natu-
ral product spectroscopic data.
Amphidinin B (2): To a vigorously stirred solution of diol 3 (2.3 g,
5.4 mmol) in CH2Cl2 (12 mL) and H2O (6 mL) was added TEMPO
(343 mg, 2.16 mmol) and BAIB (8.69 g, 26.99 mmol). Stirring was
continued until TLC indicated complete conversion of the starting
material. The reaction mixture was quenched by the addition of
saturated Na2S2O3 (40 mL), extracted with EtOAc (2ϫ70 mL) and
the combined organic layers were washed with brine (70 mL), dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(ethyl acetate/hexane, 6:4) to afford 2 (2.2 g, 90%) as a colorless
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[2]
[3]
1
liquid. [α]2D5 = –7.6 (c = 0.7, CHCl3). H NMR (600 MHz, C6D6):
[4]
δ = 5.29–5.24 (m, 1 H, RCOOCHR), 4.90 (s, 1 H, C=CH2), 4.88
(s, 1 H, C=CH2), 4.40–4.34 (m, 1 H, OCHCH2), 3.69–3.65 (m, 1
H, OCHCH3), 2.68–2.61 (m, 1 H, CH3CHCOOH), 2.60–2.48 (m,
2 H, CH2COOH and CH2C=CH2), 2.30–2.22 (m, 2 H, CH2C=CH2
and CH2COOH), 2.09 (dd, J = 14.6, 4.3 Hz, 1 H, CH2C=CH2),
2.0 (dd, J = 14.6, 3.9 Hz, 1 H, CH2C=CH2), 1.93 (dd, J = 14.9,
6.1 Hz, 1 H, OCHCHCH3), 1.82–1.75 (m, 2 H, OCHCH2), 1.56–
1.49 (m, 1 H, OCHCH2), 1.46–1.27 (m, 12 H, (CH2)6), 1.20 (d, J
= 6.7 Hz, 3 H, CHCH3), 1.04 (d, J = 6.7 Hz, 3 H, CHCH3), 0.87
(t, J = 7.3 Hz, 3 H, CH2CH3), 0.66 (d, J = 7.0 Hz, 3 H,
CHCH3) ppm. 13C NMR (75 MHz, C6D6): δ = 182.4, 177.4, 176.1,
143.3, 114.3, 81.3, 73.0, 71.5, 41.6, 41.1, 40.2, 40.1, 39.7, 38.2, 36.8,
36.1, 34.1, 30.3, 27.5, 26.8, 18.9, 17.4, 17.0, 14.1, 14.0 ppm. IR
[5]
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[8]
[9]
(neat): ν = 2924, 2854, 1714, 1460, 1174, 1083, 903, 770 cm–1.
˜
HRMS (ESI): calcd. for C25H42NaO7 [M + Na]+ 477.2828; found
477.2834.
Methyl Ester of Amphidinin B (23): To a stirred solution of amphid-
inin B (2; 1.2 g, 2.64 mmol) in diethyl ether (20 mL) at 0 °C under
a nitrogen atmosphere, was added CH2N2 generated by the treat-
ment of N-nitroso N-methyl urea (1.6 g, 15.86 mmol) with 40%
NaOH solution (15 mL). The reaction was stirred at 0 °C for
30 min and the organic layer was washed with a saturated solution
of NaHCO3 (20 mL), brine (20 mL), dried with anhydrous Na2SO4
and concentrated under reduced pressure. The crude compound
was purified by flash column chromatography (ethyl acetate/hex-
ane, 1.2:8.8) to afford methyl ester 23 (1.19 g, 94%) as a colorless
liquid. [α]2D5 = +6.2 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 5.06–4.96 (m, 1 H, RCOOCHR), 4.80 (d, J = 2.2 Hz, 2 H,
C=CH2), 4.50–4.40 (m, 1 H, OCHCH2), 3.90–3.81 (m, 1 H,
OCHCH3), 3.68 (s, 3 H, COOCH3), 3.65 (s, 3 H, COOCH3), 2.72–
2.57 (m, 1 H, OCOCHCH3), 2.47–2.09 (m, 6 H, CH2COOCH3,
CH2C=CH2, CH(CH3)COOCH3 and CH2C=CH2), 1.89–1.24 (m,
16 H, CH2C=CH2, OCHCH2CH3, CHCH3 and (CH2)6), 1.15 (d,
J = 6.8 Hz, 3 H, CHCH3), 1.11 (d, J = 6.7 Hz, 3 H, CHCH3), 0.94–
0.88 (m, 6 H, CHCH3 and CH2CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.6, 176.4, 171.7, 142.7, 114.3, 81.3, 72.9, 71.3, 51.5,
51.4, 41.4, 40.7, 40.0, 39.7, 37.9, 36.2, 35.7, 33.7, 30.1, 29.7, 27.4,
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26.4, 18.6, 17.1, 17.0, 13.9, 13.8 ppm. IR (neat): ν = 2934, 2864,
˜
1735, 1458, 1376, 1252, 1168, 1088, 1008, 901, 757 cm–1. HRMS
(ESI): calcd. for C27H46NaO7 [M + Na]+ 505.3141; found 505.3134.
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Acknowledgments
A. S. R. and C. S. R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for the award of research fel-
Received: August 26, 2010
Published Online: December 14, 2010
706
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Eur. J. Org. Chem. 2011, 696–706